Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7007—Drug-containing films, membranes or sheets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

• This invention relates to the administration of pergolide to a patient. More particularly, this invention relates to the transdermal delivery of pergolide.
• Pergolide is a drug that is used to treat various health conditions that affect individuals. For example, pergolide has been used in the treatment of the symptoms of Parkinson's disease and in the reduction of plasma concentrations of prolactin in conjunction with the treatment of hyperprolactinemia. In the treatment of Parkinson's disease, the typical course of medication is a gradual increase in the oral dose over 14 days, with a concomitant gradual increase in blood serum levels.
• Blood serum levels ranging between a maximum of about 500 picograms/ml (maximum serum level 2-3 hours following a 2.5 mg oral dose) to about 60 picograms/ml (serum level 8 hours following a 0.5 mg oral dose) have been considered within a therapeutic range from oral dosing studies of pergolide mesylate in the treatment of Parkinson's disease.
• oral dosing is 3 mg/24 hours, divided into three doses, with serum concentrations peaking at approximately 200pg/ml.
• pergolide offers the advantage of being simple to administer.
• blood serum levels fluctuate between dosages and the drug must pass through the liver before systemic distribution in the blood stream, requiring a dosage level high enough to account for metabolic losses in the hepatic system. Accordingly, there are disadvantages associated with the administration of oral doses of pergolide.
• the present invention relates to the transdermal delivery of pergolide.
• European published patent application EP 0913128A1 discloses a transdermal device for delivering a variety of medicaments, for example, pergolide.
• the device utilizes a layer of polymeric adhesive in which the medicament is dispersed homogeneously.
• the medicament-containing adhesive layer is prepared by dissolving the constituents in a solvent(s). The resulting solution solidifies to form the medicament-containing layer upon evaporation of the solvent.
• the device includes also a backing layer on one side of the adhesive layer to protect the adhesive layer during use and storage and a strippable release layer on the other side of the adhesive layer to protect the otherwise exposed side of the adhesive layer during storage. The strippable layer is removed before application of the adhesive layer of the device to the body membrane.
• Transdermal delivery of pergolide is disclosed also in U.S. Patent No. 6,001 ,390 to Yum.
• the '390 patent discloses the delivery of pergolide mesylate in vitro across samples of human skin.
• a liquid pergolide-containing composition is held within the device in a space from which the pergolide is delivered to the body membrane by diffusion through a micro-porous membrane in contact therewith.
• the device includes a strippable layer which covers the face of the micro-porous membrane that is placed in contact with the body membrane and which is removed at the time of use.
• the pergolide is contained in a solid polymeric film which is prepared by forming a solution of the pergolide and polymeric carrier and evaporating the solvent to form the polymeric film.
• the present invention relates to improved means for the transdermal delivery of pergolide to a patient.
• a transdermal delivery device comprising a multi-phase matrix which includes a solid liquid-retaining member and associated therewith pergolide in liquid form.
• the liquid-retaining member is, for example, a non- woven medical absorbent and the pergolide is dissolved in an aqueous based solvent.
• Another aspect of the present invention is the provision of a method for the transdermal delivery of pergolide comprising delivering to a body membrane pergolide in liquid form and from a liquid pergolide-carrying member which is in direct contact with the body membrane.
• the pergolide is delivered from a supply source directly to the body membrane unimpeded by a material interposed between the source and the surface of the body membrane.
• the present invention provides the means to efficiently deliver relatively high amounts of pergolide transdermally and to achieve desired blood serum levels of the pergolide. And this can be accomplished without irritating the membrane of the patient.
• Figures 1 to 4 are graphical representation of in vitro pergolide delivery flux from a transdermal delivery device of the present invention.
• Figure 5 is a graphical representation of in vivo pergolide blood serum levels attained by a transdermal delivery device of the present invention.
• Figure 6 is a graphical representation of in vitro pergolide delivery flux involving the use of a comparative composition comprising a solid solution of pergolide.
• Figures 7 to 9 are graphical representations of in vitro pergolide delivery flux from direct application to the skin of a liquid pergolide composition. Detailed Description of the Invention
• the present invention relates to the transdermal delivery of liquid pergolide from a transdermal delivery device held in contact with a membrane of an animal to which pergolide is to be delivered.
• the delivery device of the present invention comprises a multi-phase matrix which includes a solid material for holding the liquid pergolide.
• the device may include other elements which relate to the use or functioning of the device. Examples of such elements are a layer to secure the device in place during use, a barrier layer on that surface of the matrix which is not in contact with the body membrane to prevent the liquid pergolide from exiting that surface, and a release layer which shields the other surface of the matrix from the ambient when the device is not in use.
• the multi-phase matrix of the delivery device has at least two elements, pergolide in liquid form and a solid material which has an affinity for the liquid and so functions as a liquid-retaining member.
• the affinity between the composition comprising the liquid pergolide and the solid liquid-retaining member may be due, for example, to adsorption such as physi- or chemi-sorption or to absorption within void spaces in the material.
• the liquid pergolide is contained in a composition which can include other constituents, as described below.
• the composition is held by the liquid-retaining member with sufficiently strong force to withstand pressure that the device may be subjected to in the ordinary course of use and handling without expelling the composition therefrom.
• the liquid-retaining member of the delivery device of the present invention can be made of any suitable material.
• the material should exhibit an affinity for some or all of the components of the composition which comprises the liquid pergolide.
• the material should not irreversibly react or interact with any of the components of the composition. For example, it should resist being degraded by the composition. Conversely, the material should not affect adversely any components of the composition.
• materials which are inert toward the components of the composition and do not dissolve therein are suitable materials for use in fabricating the liquid-retaining member.
• suitable materials are reticulated materials represented by the natural and synthetic fibers in the form of woven gauze, relatively long staple absorbent masses, non- woven fiber web, and a non- woven web which is surface-treated with a porous polymer.
• a preferred material is a non- woven material comprising rayon web covered with porous polyethylene, for example, 1603 non- woven medical absorbent available from 3M.
• Such materials are capable of retaining the composition comprising the liquid pergolide in cavities, pores or channels that comprise the materials.
• the liquid- retaining member can also comprise a material which adsorbs the liquid pergolide.
• a surface of a component of the liquid composition can be adsorbed to a surface of the material comprising the liquid-retaining member and, by cohesive interaction with un-adsorbed components of the liquid composition, the bulk of the composition is retained by the member.
• the solid liquid-retaining member of the delivery device of the present invention has associated therewith pergolide in liquid form.
• pergolide is used herein to mean any pharmaceutically acceptable species of ergoline having pharmaceutical properties like those of the free base 8 ⁇ -[(methylthio)methyl]-6-propyl ergoline. It is recognized that there are many species of pergolide which are suitable for the treatment of abnormal bodily conditions, for example, treating the symptoms of Parkinson's disease and hyperprolactinemia.
• acid salts of the free base and compounds which have structural variations of the ergoline ring are known to be pharmaceutically active.
• pergolide mesylate and pergolide free-base are a solid at room temperature and are sufficiently soluble in water or nonaqueous solvents to provide a solution which contains pharmaceutically effective amounts of the dissolved pergolide species.
• the matrix of the delivery device will typically contain a composition which comprises a "pergolide" solvent in addition to the pergolide. It is likely that a solvent will be used also with those pharmaceutically acceptable species of pergolide that are liquids under ambient conditions to function as a diluent or carrier of the liquid pergolide
• liquid solvent inorganic or organic
• suitable liquid solvent capable of dissolving the pergolide in an amount which is considered sufficient for including in the matrix of the delivery device
• Water, alcohols, for example, ethanol, dimethyl sulfoxide (DMSO), and glycols, for example, polyethylene glycol and polypropylene glycol are examples of solvents that can be used.
• pergolide solvent serves also as a diluent and functions to reduce undesirable irritation.
• the solvent can act also to improve the permeability of the skin or mucous membrane to the pergolide.
• the solvent can function as a diffusion media which helps to conduct the pergolide to the body membrane through which it enters the body.
• the pergolide-containing composition can comprise a single phase composition, for example, a liquid solution of pergolide, or it can comprise a multi-phase composition, for example, an emulsion, a gel, or a dispersion which includes the pergolide in liquid form.
• An emulsion can comprise liquid droplets of a solution of pergolide dispersed in a continuous liquid phase
• a gel can comprise a phase of continuous solution thickened by an appropriate gelling agent which comprises a dispersed phase.
• a dispersion can comprise a liquid solution of dissolved pergolide having dispensed therein solid particles of pergolide, for example, nanoparticles of pergolide.
• the composition comprises a solution of pergolide having a viscosity at room temperature such that the solution flows readily, for example, from a pipette which is used to deliver the solution to the liquid-retarning member of the matrix.
• aqueous-based solution which includes a hydrocarbon-based solvent is particularly preferred.
• the pergolide-containing composition can include one or more additives which function to impart desired properties to the composition.
• the composition can include a co-solvent to improve the solubility of the pergolide in the principal solvent.
• the use of an alcohol as a co-solvent to improve the solubility of pergolide in water is exemplary.
• the composition can include an enhancer which functions to enhance the ability of the pergolide to be delivered transdermally. Examples of enhancers are alcohols, glycols, fatty acids, and fatty acid esters.
• Another example of an additive is a thickening agent, for example, hydro xymethyl cellulose, which functions to impart to the composition a desired viscosity.
• exemplary additives are, for example, stabilizers, preservatives, and antioxidants.
• a stabilizer is an art-recognized compound defined in the " Handbook of Pharmaceutical Additives," Ash, Michael and Irene, Gower 1995, to be a pharmaceutical additive that thickens, prevents separation, retards oxidation by increasing viscosity, and gives a smoother product.
• An antioxidant is also an art- recognized compound and is defined by the Handbook of Pharmaceutical Additives to be a substance that retards oxidation, deterioration, rancidity, and gum formation in organic substances.
• a preservative is also an art-recognized compound defined by the Handbook of Pharmaceutical Additives to be a substance, either natural or synthetic, that protects a pharmaceutical composition against spoilage, discoloration, or decay and is used to retard or prevent microbial or chemical spoilage.
• compositions of the present development can include also one more of such compounds.
• Some additives may improve more than one property of the composition. For example, DMSO may enhance the solubility of the pergolide and its ability to be delivered transdermally.
• additives of the type referred to herein, as well as other additives for use in pergolide compositions are known. Accordingly, it should be understood that compounds other than those referred to above can be used in the pergolide-containing composition. In preferred form, the additives are present in dissolved form in the composition.
• the amount of pergolide comprising the composition should be an amount sufficient to deliver transdermally a pharmaceutically effective amount of pergolide to the body. Such amount will vary depending on numerous factors, for example, the species of pergolide used, the condition to be treated, the nature of the material comprising the liquid-ret-aining member of the matrix, and the area of the matrix surface which is in contact with the body membrane. It is believed that a composition comprising about 0.1 to about 10 wt. % of pergolide will be effective for most applications. However, it should be understood that there may be applications where the composition comprises a lower or higher proportion of pergolide.
• any particular additive comprising the composition will depend on numerous factors. For most applications, it is believed that the additive will typically comprise about 0.01 to about 50 wt. % of the composition. Lower or higher amounts can be used, depending on the particular additive and the involved application.
• an additive such as a stabilizer, preservative, or an antioxidant can comprise about 0.4 to about 2 wt. %of the composition.
• a preferred composition comprising about 90 to about 96 wt. % water, about 0.4 to about 2 wt. % ⁇ -cyclodextrine, about 3 wt. % to about 6 wt. % hydroxy propyl cellulose, and about 0.1 wt. % to about 1 wt. % pergolide mesylate is particularly useful both as a form of liquid pergolide and as a base composition to which stabilizers, antioxidants, and preservatives can be added to yield a liquid pergolide composition.
• an antioxidant for example, about 0.05 to 0.4 wt. % ascorbic acid and/or citric acid
• a preservative for example, about 0.05 to about 4 wt. % benzyl alcohol and/or lactic acid
• Another preferred composition includes up to about 5 wt. % ethyl alcohol (for example, about 1 to about 5 wt. %) which can be added to the base composition as a preservative and co-solvent and to which additional antioxidants, stabilizers, and preservatives can be added to yield a composition which is particularly stable.
• the matrix of the present invention may be prepared by selecting a liquid- retaining material which has a suitable affinity for the pergolide-containing composition, forming it or cutting it into a desired shape which has surface area of desired magnitude and applying, to the material the desired amount of composition.
• the composition can be applied to a bulk of the liquid-retaining material which is then shaped or cut to the desired size.
• Any suitable shape of retaining material can be used.
• the material is in the form of a disk or pad having two faces and an edge.
• the transdermal delivery device of the present invention can include other elements of the type that are normally present in transdermal delivery devices including, for example, a barrier layer which covers one of the faces of the matrix, a layer which holds the device to the body surface to be treated, and a removable layer that protects the other face of the matrix and which can be removed when the device is ready for use.
• the liquid-retaining material of the matrix is in direct contact with the body membrane during use.
• a permeable layer for example, a microporous membrane, through which the pergolide is capable of flowing on its way to the body surface and which covers that face of matrix membrane which faces toward the body membrane.
• the face of the permeable layer not in contact with the face of the matrix which can be covered with the removable layer.
• transdermal delivery devices were fabricated and pergolide delivery flux was determined from their use in separate in vitro and in vivo measurements.
• In vitro measurements of pergolide delivery flux in all cases were carried out using a diffusion cell to which samples of human skin were fixed such that the stratum corneum was accessible for application of the delivery device or of a composition comprising pergolide in liquid form.
• a skin sample was fastened onto a diffusion cell filled with saline solution as a receiver liquid.
• a transdermal delivery device of the present invention was applied to the stratum corneum of the affixed sample, the cell was placed in an environment in which an even temperature was maintained throughout the evaluations.
• the diffusion cell was equilibrated for, a predeterminted time then a sample of the receiver liquid was withdrawn to establish a baseline. Subsequent samples of receiver liquid were removed at predetermined time intervals.
• the first group of examples are illustrative of transdermal delivery devices of the present invention. They include a multi-phase matrix comprising a liquid-retaining material in the form of disks of the various materials listed below in Table 1 (Example Nos. 1-8) and a phase of pergolide in liquid form covering an area of 1 cm 2 .
• the liquid pergolide used in the devices of Example Nos. 1-5 of Table 1 was a viscous liquid composition comprising 0.48 wt. % pergolide mesylate, 0.8 wt. % ⁇ -cyclodextrin, 3.0 wt. % hydroxypropyl cellulose, and 95.7 wt. % water; this is a particularly preferred composition.
• the device of Example No. 6 included a liquid composition comprising 0.5 wt. % pergolide mesylate, 3.0 wt. % hydroxypropyl cellulose, and 96.5 wt. % water.
• the device of Example No. 7 included a liquid composition comprising 0.55 wt. % pergolide mesylate, 6.0 wt. % hydroxypropyl cellulose, and 93.45 wt. % water
• that of Example No. 8 included a composition comprising 0.05 wt. % pergolide mesylate and 99.95 wt.
• compositions used in the transdermal devices of the examples were made by dissolving solid particles of pergolide mesylate in deionized water and adding ⁇ cyclodextrin (if used) and hydroxypropyl cellulose (if used) to yield the wt. % composition listed.
• the compositions were of sufficiently low viscosity to be dispensed onto the liquid-retaining material from a conventional pipette.
• All of the examplary transdermal delivery devices described herein were fabricated by forming the selected liquid-retaining material into a desired shape and area (for example, a pad or a disk) and then laminating one face of the shaped material to a section of 9732 polyester film (3M) which functioned as a barrier layer.
• the film was sized so that the barrier layer of the resulting laminate extended beyond the edges of the retaining material.
• the laminate was affixed to the adhesive face of 9772 PNC foam tape (3M) such that the barrier layer was interposed between the tape and the material.
• the PVC foam tape was sized to extend beyond the edges of the barrier layer so that the tape functioned as an adhesive layer to hold the laminate in contact with a membrane to which the device was applied.
• the pergolide composition was applied to the exposed surface of the retaining material over a controlled area of surface.
• the area to which the pergolide composition was applied was selected to give an area of desired size over which transdermal delivery could occur (active area).
• the pergolide composition was applied in an amount of 70 ⁇ l / cm 2 of the selected area.
• the devices of Example ⁇ os. 6 and 7 contained 0.89 mg pergolide mesy late/cm 2 of liquid-retaining materials and that of Example No. 8 contained 0.07 mg pergolide mesylate /cm 2 of liquid-retaining material .
• the area stated for the liquid-retaining material is the area of the pad to which the liquid composition was applied measured as superficial area.
• pergolide can be delivered from a transdermal delivery device of the present invention at a delivery flux commensurate with establishing therapeutic blood serum levels of pergolide.
• the next group of examples illustrate the use on human subjects of delivery devices similar to those described above.
• the liquid-retaining material of the devices comprised pads of 1603 non- woven medical absorbent (3M) having surface areas sufficient to have a liquid form of pergolide applied to a 10 or 30 cm 2 area.
• the devices included the same composition as that used in the devices of Example Nos. 1-6 of Table 1 (0.48 wt. % pergolide mesylate, 0.8 wt. % ⁇ -cyclodextrin, 3.0 wt. % hydroxypropyl cellulose, and 95.7 wt. % water). Twelve devices having a 10 cm 2 active area and 4 devices having a 30 cm 2 active area were prepared.
• One device having a 10 cm 2 active area was applied to four subjects. Four other subjects received two devices each having a 10 cm 2 active area, and four other subjects each received a device having a 30 cm 2 active area. The devices were applied to the skin on the upper outer arm of human subjects. Blood samples were drawn from test subjects at regular intervals and tested for pergolide levels. Pergolide blood serum levels were determined by subjecting blood samples to liquid chromatography using mass spectroscopic detection according to testing protocol #AN47849-101-PPD.
• transdermal devices of the present invention deliver therapeutic levels of pergolide mesylate.
• transdermal devices applied to human subjects did not produce skin irritation at the site of application.
• Transdermal devices having a matrix comprising pergolide base and enhancers were fabricated by blending pergolide free base and enhancers into aliquots of acrylate-based pressure sensitive adhesive (PSA) and casting the composition into a film in which the pergolide free base was present as a solid solution.
• Cast film matricies were prepared using National starch adhesives 87-2074 (Matrix A), 87-2620 (Matrix B), and 87-2696 (Matrix C) and Monsanto Adhesive 2873 Gelvea multipolymer acrylic resin (Matrix D).
• Matricies A, B, and D had a composition of 2 wt. % pergolide free base and 98.0 wt. % of the respective PSA used.
• the composition of Matrix C was 5 wt. % pergolide free base and 95 wt. % of the PSA used.
• the cast films were adhesive to skin as cast.
• cast films were cut into 1 cm 2 units.
• the pergolide delivery flux available from these cast film matricies was determined by adhering a laminate containing a 1 cm 2 unit to a sample of human skin mounted on a diffusion cell according to the in vitro testing procedure described above.
• compositions which can be used in the practice of the present invention.
• the compositions are identified in Table 4 below.
• the compositions were prepared by placing a weighted amount of the indicated solvent or solvents into a suitable mixing vessel and adding solid pergolide mesylate in the form of anhydrous powder and the additives identified in Table 4 into the solvent with stirring at 25 °C until the solid constituents dissolved.
• the various compositions prepared are reported in Table 4 as wt. % of the listed constituents.
• HPC hydroxypropyl cellulose
• PVA poly(vinyl alcohol) 4.
• DMSO dimethyl sulfoxide
• composition D (Table 5), which contains no water, was applied to a 1 cm 2 pad of 1603 non-woven medical absorbent (3M) and fixed to a skin sample mounted on a diffusion cell.
• An in vitro determination of the delivery flux from this patch showed a peak flux of 0.05 ⁇ g/ cm 2 hr of pergolide after 21 hours.
• the compositions of Table 5 can be used in a transdermal delivery device to treat patients.

Landscapes

• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Neurology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Hematology (AREA)
• Diabetes (AREA)
• Psychology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=23073490

Family Applications (1)

Country Status (4)

Families Citing this family (21)

Family Cites Families (2)

• 2002
  • 2002-04-01 JP JP2002576871A patent/JP2005506297A/ja active Pending
  • 2002-04-01 CA CA002443128A patent/CA2443128A1/en not_active Abandoned
  • 2002-04-01 EP EP02757900A patent/EP1385459A2/de not_active Withdrawn
  • 2002-04-01 WO PCT/US2002/010057 patent/WO2002078602A2/en not_active Ceased

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events